Older people are disproportionally affected by various chronic illnesses, typically related to frailty and metabolic syndrome. Both conditions cannot be cured but may be delayed by lifestyle changes. For instance, exercise increases muscle mass, enhances insulin sensitivity, and improves median survival. However, exercise is not always feasible for aged individuals. Hence, development of molecular approaches to mimic the health benefit of exercise can be especially important in order to delay age-related physical and metabolic dysfunction. The goal of this work is to test whether myostatin blockade can be viewed as such a useful exercise mimetic. We hypothesize that blocking myostatin, an endogenous inhibitor for muscle development, at late middle age will increase muscle mass and delay sarcopenia. While this hypothesis is supported by extensive previous studies with myostatin knockout and inhibitors in young animals, proof-of-concept within the context of aging is missing. This knowledge gap will be filled by the results from this work. In addition, based on our novel preliminary findings of interactions between myostatin and hepatocytes in cell culture, we propose a second hypothesis that liver can be a direct target of myostatin blockade. This explains the prior findings of improved liver function in myostatin knockout mice and our preliminary data showing decreased diet-induced hepatosteatosis in mice treated with myostatin inhibitory propeptide. Solid evidence to support this hypothesis, as will be collected in this work, will shift the paradigm of myostatin studies from exclusively muscle-focused to include liver and possibly other organs. This may bring novel opportunities for myostatin-based therapeutic developments to treat metabolic diseases. We will test our hypothesis using a wild-type mouse model beginning at late middle age, with myostatin blockade achieved by one-time injection of adeno-associated virus (AAV) encoding a myostatin-specific inhibitor, the propeptide mutant. Animals will be tested in parallel with standard low-fat and isocaloric high-fat diets, following two specific aims. Aim-1 will focus on in vivo assessment of metabolic and functional performance at different points of aging, including measurement of respiration, insulin sensitivity, strength and endurance, as well as median and maximum lifespan. Aim-2 will focus on muscle- and liver-specific signaling, mitochondrial activity, protein synthesis, and lipid metabolism. PUBLIC HEALTH RELEVANCE: The proposed research will determine if and how blocking myostatin, a muscle-secreted negative regulator for muscle development, will delay age-associated metabolic and functional decline. This work is directly relevant to the mission of NIH to pursue knowledge to extend healthy life and reduce burdens of illness and disability.